Hydrogen-bonded Trimers of DNA Bases and their Interaction with Metal Cations: Ab initio Quantum-chemical and Empirical Potential Study

Abstract

Neutral (G.GC, A. AT, G.AT, T. AT, and C (imino).GC) and protonated (CH⁺.GC and AH⁺.GC) hydrogen-bonded trimers of nucleic acid bases were characterized by ab initio methods with the inclusion of electron correlation. In addition, the influence of metal cations on the third-strand binding in Purine-Purine-Pyrimidine (Pu.PuPy) reverse-Hoogsteen triplets has been studied. The ab initio calculations were compared with those from recently introduced force fields (AMBER4.1, CHARMM23, and CFF95). The three-body term in neutral trimers is mostly negligible, and the use of empirical potentials is justified. The only exception is the neutral G.GC Hoogsteen trimer with a three-body term of -4 kcal/mol. Protonated trimers are stabilized by molecular ion—;molecular dipole attraction and the interaction within the complex is nonadditive, with the three-body term on the order of -3 kcal/mol. There is a significant induction interaction between the third-strand protonated base and guanine. The calculations indicate an enhancement of the third-strand binding in the G.GC reverse-Hoogsteen trimer due to metal cation coordination to the N7/06 position of the third-strand guanine. Interactions between metal cations and complexes of DNA bases are in general highly nonadditive; the three-body term is above -10 kcal/mol in a complex of a divalent cation (Ca²⁺) with the GG reverse-Hoogsteen pair. The pairwise additive empirical potentials qualitatively underestimate the binding energy between cation and base.